Ethers of 7-hydroxyphenothiazone-3



Patented Apr. 25, 1959 7 ETHERS OF 7-HYDROXYPHENOTHIAZONE-3 "David F. Houston, El Cerrito, and Ernest B. Kester, Berkeley, Calif., assignors to the United States of America as represented by'the Secretary of Agriculture N Drawing. Application August 23, 1949, Serial No. 111,963

7 Glaims. (01. 260-243) (Granted under the act of March 3, 188.3, as

1 This application is made under .the act of March .3, 1883, as amendedlby the. act ofApril so,

.1928, and the invention herein described, if

patented in any country, may be .manufactured and used by orior the Government of the United .States of America vforgovernmental purposes "throughout .the'world without thev payment to us 0'1 any royalty thereon.

This application relates to .alkyl ethers :of '7 hydroxyphenothiazone-3 wherein the alkyl radical contains atleast 5 carbonatoms. These "compounds can be represented by the formula wherein R is an alkyl radical containing at least 5 carbonatoms.

The alkyl ethers in accordance with this inventionare red ororange red crystallinesolids which are useful as dyestuffs, pigments, andas intermediates .for-the preparation of other dyestuffs. They are water-insoluble but are soluble in fat solvents and other lipophilic materials, thus they may be used as coloring-agents forgasoline, lubricating oils, greases, plastics, etc. Further, these alkyl ethers have bacteriostatic properties, for example, against Mycobacterium tuberculosis (in vitro).

The objects of this invention include: the provision of novel compounds, namely alkyl ethers of '7-hydroxyphenothiazone-B and also the provision of methods for preparing-and purifying these compounds. Further objects will be apparent from the description herein.

The novel ethers of this invention are prepared by reacting the silver salt of '7-hydroxyphenothiazone-3 with an allzyl iodide. The particular alkyl iodide determines the type of ether produced, thus if n-amyl iodide is used, the n-amyl ether is produced. Other alkyl iodides which may be used are hexyl iodide, heptyl iodide, octyl iodide, nonyl iodide, decyl iodide, undecyl iodide, dodecyl iodide, tridecyl iodide, tetradecyl iodide, pentadecyl iodide, hexadecyl iodide, heptadecyl iodide, octadecyl iodide, and so forth. The alkyl radical need not be a straight-chain (normal) radical but may be branched so that one can also use 3-methyl pentyl iodide, isoamyl iodide, 2-ethyl hexyl iodide, and so forth. The alkyl iodide reagent is generally employed in excess whereby the reaction proceeds faster; the unreacted alkyl iodide can be recovered from the reaction mixture by suitable techniques such as distillation. The

amended "April'30, 1928; 3.7.0 0. G. .757)

ether-ification is carried out at an elevatedtemperature from about 50 C. to 200 C. It is preferred to carry out the :etherification in a solvent and reflux the solventduring the reaction. Suitable solvents are benzene, toluene, xylenes, or other inert, organic, hydrophobic solvents. After the etherification is complete theproduct can be recovered by filtration and evaporation of the solvent and by vacuum distillation :to remove the excess alkyl iodide. If, however, the product is desired in pure form then it is preferred to carry out an adsorption.and'elution. Tothis end, the filtered reaction mixture. is contacted 'with a solid adsorbent material such as alumina, activated carbon, bentonite, or the like. The ether is adsorbed on the surface of the adsorb-entby this "treatment. The adsorbent material is then washed with a solvent and by observing the-color oi the washsolvent the product may be separated. Thus only the solvent efiiuents are collected which are red in color, *sincethose contain the desired ether. The other fractions are discarded since they contain the impurities. The red solvent fractions are then subjected to evaporation to recover the-ether in solid form. Forthe purpose of eluting the adsorbent one can use benzene,

ohloroformgmixtures of benzene and chloroform,

toluene, xylene, carbon tetrachloride, ethylene dichloride or other inert, organic hydrophobic solvent.

The following examples demonstrate specific techniques Within the scope of this invention. It is understood that these examples are furnished only by Way of illustration and not limitation.

EXAMPLE I (a) Preparation of silver salt of 7-hydroryphenothia2one-3 2.35 grams (0.01 mole) of the lithium salt of 7-hydroxyphenothiazone-3 was dissolved in one liter of hot water. 2.5 grams (0.015 mole) of silver nitrate, dissolved in ml. of water was added and the reaction mixture digested on the steam bath for one hour. The silver salt was then separated by filtration, washed, and dried at C.

(b) Preparation of 7-n-amyloazyphenothz'aeone-3 The silver salt as obtained in step a was dispersed in 500 m1. of benzene together with 9.9 grams (.05 mole) of n-amyl iodide. The mixture was refluxed for 7 hours then filtered, the filtrate being retained. The solid material remaining on iodide, and n-hexadecyl iodide, respectively. The following results were obtained.

the filter was washed with 200 cc. of hot benzene, the wash liquid being added to the first filtrate.

Ethers of 7-hydroxyphenothz'azone-3 Analytical data Cole. data Alkyl group of Color Yield, Meltin Percent point a 0, Per- H, Per- N, Per- 0, Per- H, Per- N, Percent cent cent cent cent cent n-octyl garnet red... 53 115. 5-116 70. 8 6. 88 4. 02 70. 33 6. 79 4. l n-dodecyl do 52 121 1 22. 5 72. 9 7. 88 3. 47 72. 5 7. 86 3. 52 n-hexadccyl orange red... 44 120. 5-121. 5 74. 8. 65 3. 04 74. 13 8. 66 3. 00

The combined liquid phases contained a yield of Having thus described the invention, what is 40% of the crude 7-n-amyloxyphenothiazone-3. claimed is:

(c) Purification The benzene solution from part b was poured through a cylinder cm. long and 3.3 cm. in diameter, which was filled with granules of activated alumina. The amyl ether was adsorbed on the alumina by this treatment in a broad red band. A series of solvents, namely, 250 ml. benzene, 1000 ml. benzene-chloroform (9:1), and 2500 ml. benzene-chloroform (4:1), were passed through the cylinder to move the red band of the amyl ether through the alumina and finally wash it out. In these washings only those portions of the solvents which were colored red were retained.

1. An alkyl ether of 'l-hydroxyphenothiazone-B wherein the alkyl radical contains at least 5 carbon atoms.

2. '2-amyloxyphenothiazone-B.

3. 7-octyloxyphenothiazone-3.

4. 7-hexadecyloxyphenothiazone-3.

5. A process for preparing a 'Z-alkoxyphenothiazone-3 which comprises reacting the silver salt of 7-hydroxyphenothiazone3 with an alkyl iodide containing at least 5 carbon atoms.

6. A process for isolating an alkyl ether of 7-hydroxyphenothiazone3 from an impure solution thereof which comprises contacting the solution with a solid adsorbent material, washing the s of P impllrities origmany present were treated adsorbent material with an organic, hyd1solveclfl 1n E'1leddl7S0glg8d pogtionihof the s 31ve drophobic solvent and collecting the fraction of zgs g pi g i ggg i ga igfiggg zg till-e1 solvent wash liquid which contains the alkyl at the 9 the 9 The portion of the e fi l e process for preparing an alkyl ether of lized from hexane-benzene and acetone A yield acting Silver Salt- 0? 7thydroxyphenothiof 25% of 7 amyloxyphenothiazone 3' was azone-3 w th an alkyl iodide 1n the presence of tamed as gamet red lathlike crystals M P refluxing benzene, passing the resulting benzene 124 C Analysis C 68 2% H M solution of the alkyl ether through a bed of 4 6 (calchlatedz 5 5 alumina, washing the bed with chloroform- 4:68% benzene and collecting the fraction of the wash EXAMPLE II solvent which contains the alkyl ether.

DAVID F. HOUSTON. The process of Example I was repeated, sub- RNEST B, KESTER stituting for n-amyl iodide stoichiometrically equivalent amounts of n-octyl iodide, n-dodecyl No references cited. 

1. AN ALKYL ETHER OF 7-HYDROXPHENOTHIAZONE-3 WHEREIN THE ALKYL RADICAL CONTAINS AT LEAST 5 CARBON ATOMS. 